In recent years great advances and important new discoveries have been made in immunology in general and in the development of new or more potent vaccines in particular. A better understanding of some of the underlying principles is beginning to emerge in the art, but many phenomena and mechanisms related thereto are still not understood or are understood incompletely only. Some aspects of the state of the art relating to adjuvants are well summarized in a recent article by Audibert and Chedid, entitled "Recent Advances Concerning the Use of Muramyl Dipeptide Derivatives as Vaccine Potentiators" in "New Developments with Human and Veterinary Vaccines" (1980) Allen R. Liss, Inc., 150 fifth avenue, N.Y.1001, page 325-338, wherein it is stated: "There exists a general consensus for the requirements of adjuvants in the following cases: (a) prolonging the efficacy of immunization; (b) avoiding the need for repeated injections; (c) decreasing the dose of antigen to reduce side effects and/or its costs; (d) increasing the immunogenicity or (e) augmenting the immunological responsiveness of certain hosts; (f) obtaining more selective responses." In the conclusions these same authors state: "It can be assumed reasonably that many new vaccines will contain two kinds of well-defined components, a specific antigenic stimulus and a non-specific adjuvant. Until very recently immuno potentiating engines [sic] were complex and ill-defined."
The classical example of a highly effective adjuvant for eliciting a strong and persistent immuno response to an injected immunogen (which is inter alia also discussed in the above article) is Freund's complete adjuvant, a combination of a mineral oil emulsion and mycobacteria. Also well-known in Freund's incomplete adjuvant which differs from the complete adjuvant in that it lacks the mycobacteria component. Both adjuvants are used extensively in veterinary medicine and for the immunization of laboratory animals in order to produce antibody preparations for use, e.g. as antisera or immuno reagents (such as diagnostics). However, neither of these adjuvants is acceptable for clinical purposes in humans, because of the presence of mineral oil and in the case of Freund's complete adjuvant also because of side effects resulting from the mycobacteria, in particular necrosis at the injection site. These factors naturally also are to be considered disadvantageous when treating animals. Other adjuvants which achieve a prolonged immunogenic response are protein adsorbents such as aluminum hydroxide or aluminium phosphate, used for example in influenza vaccines. However, these substances which achieve a slow release effect have the disadvantage of being foreign to the body. They do not contribute to the immunogenicity of the immunigen itself, once the immunogen is released from adsorption.
It is known to improve the immunogenicity of immunogens or to impart immunogenicity to haptens which on their own are immunogenically inactive, by covalently aggregating these haptens or immunogens or linking them covalently to carrier molecules or particles such as proteins in order to produce immunogenic particles of increased size and having specificity for the hapten or immunogen. For example, H. Gharib et al (J.Clin. Endocrinol. and Metabolism (1971) 33, 509-516) describe the covalent linking of T.sub.3 to serum albumin derived from various animal species (human, bovine, rabbit) and using the resulting conjugates to elicit antibodies against T.sub.3 in rabbits for use in radio-immuno assays (RIA). These conjugates, however, have a short half-like, being soon destroyed in the body of the animal. Accordingly, frequent repetitions of the immunizing injections (weekly) are necessary until the required antibody level is attained and booster injections are necessary thereafter.
In the aforegoing context it is also known to covalently link haptens or immunogens by a variety of difunctional linking agents to bacterial cells or particles, preferably stripped of their natural immunogenic determinants ("naked bacteria") to produce improved immunogens. The substantial improvements in immunogenicity thus attained is believed to be due to the increased particle sizes as well as an adjuvant effect of the bacterial components(s) (UK published patent application No. GB 2,101,630 A in the name of the present applicant).
Others, e.g. the aforesaid authors Audibert and Chedid propose as an alternative new generation of adjuvants certain muramyl dipeptide derivatives (MDP - cf Audibert et al,loc.cit.). MDP represents part of the bacterial glycopeptide. Even these new adjuvants represent substances foreign to the host body, and pyrogenicity has been observed. Certain derivatives are also immunogenic on their own, i.e. have the property of sensitizing to MDP. Some toxicological criteria pertaining to the use of these adjuvants, e.g. auto-immune or allergic reactions following the administration of vaccines comprising MDP are still unknown.
Accordingly it is clear that there still exists a long felt need for adjuvants which overcome or mitigate all or at least some of the aforesaid disadvantages and/or which offer novel advantages.